Oroshnik



Sept. 9, 1952 w. OROSHNIK 2,610,185

2-AMINO-4-DIALKYLAMINOETHOXYPYRIMIDINES Filed NOV. 7, 1950 2 SHEETS-SHEET l T1 g1. T4 :12.

I 0 b Q b Fig.3.

l I a b I INVENTOR .W/LL/AM OROSHN/K.

S p 9, 1952 w. OROSHNIK 2,610,186

2-AMINO4DIALKYLAMINOETHOXYPYRIMIDINES "Fig.7.

Filed Nov. '7, 1950 2 SHEETS SHEET 2 Fig.5.

' INVENTOR W/LL/AM OPDSHN/K.

Paten te cl Sept. 9, 1952 William Oroshnik, Plainfield, N. .L, assignor to Ortho Pharmaceutical Corporation, a corporation of New Jersey Application November 7, 1950, Serial No. 194,531

This invention relates to certain therapeutically eiiective organic compounds which are derivatives of isocytosine, 2-amino-4-hydroxypyrimidine and to their use as therapeutic agents having the ability to depress contractions of the uterus. More specifically this invention relate to Z-amino- 4 dialkylaminoethoxypyrimidines and 2 amino 4 dialkylaminoethoxy 6 methylpyrimidines in which each alkyl group is an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms. The said isocytosine derivatives having the ability to depress contractions of the uterus may be represented by the following graphic formula:

l R NEE-C .\CLO-CH2-CH2N/ N C--H in which R and R" are each an isobutyl radical or an aliphatic radical having more than four and less than nine carbon atoms, and in which R" is hydrogen or methyl.

A number of derivatives of isocytosine have been prepared and studied for various pharmaceutical and medicinal uses but it is believed that the particular derivatives of isocytosine with which this invention is concerned are new substances. It is also believed the ability of these substances to depress contractions of the uterus has not been known heretofore.

The derivatives of isocytosine which embody this invention may be used as such to depress contractions of the uterus. They may also be used as in the form of salts of the isocytosine derivatives with organic or inorganic acids and since the said derivatives are basic in character, they may be readily converted into salts having substantially more solubility in water than the free bases. Salts such as the succinate, maleate,

tartrate, lactate, fumarate and the like are preferred, but salts of simple low-molecular weight aliphatic organic acids as well as salts of the free bases with inorganic acids, may be readily prepared from the free bases and are highly. effective therapeutically.

The new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products. The ability of these novel substances to depress contractions of the uterus has been 6 Claims. (01. see-256A) shown by a number of experiments in which a salt of the isocytosine derivative was added to a bath of nutrient solution having a strip of albino rat uterine tissue suspended therein. A continu ous kymographic record was made of contractions of the uterine strip before and after addi tion to the bath of a salt of an isocytosine derivative. Additional derivatives of isocytosine which are homologues of the class of isocytosine derivatives specifically mentioned before as having therapeutic value were also tested in the same way to determine their effect on contractions oi the uterus. The'succinate salts or the hydrochloride salts of the following compounds were tested for their pharmacologicalproperty of depressing contractionsof the uterus:

Compound 1-2-amino-4-diisobutylaminoethoxypyrimidine v p Compound II-2 amino-l-di-n-amylaminoethoxypyrimidine Compound III-2 amino-4-diisoamylaminoethoxypyrimidine Compound IV2-amino 4 diisooctylaminoethoxypyrimidine Compound V2-amino 4 diisobutylaminoethoxy-6-methylpyrimidine Compound .VI--2 amino-4-di-n-amy1aminoethoxy-G-methylpyrimidine Compound VlI2-amino 4 dimethylaminoethoxypyrimidine Compound VIII-2-amino 4 diethylaminoethoxypyrimidine Compound IX-2-aminol-diethy1aminoethoxy- G-methylpyrimidine V The following procedure was employed in test" ing the effect of. compounds LIX on. a rat uterus: A female albino rat weighing from 150-390 milligrams was killed by a blow on the head and the uterus was removed. A strip of the uterine tissue was suspended in a cc. bath of an aerated Ringer-Locke solution. One end of the uterine strip was maintained in a stationary position and the other end was attached to a lever which made contact with a kymograph and con tinuously recorded contractions. After a short period of immersion in the bath, the strip of uterine tissue was contracting rhythmically and normally, and at this point an aqueous solution of a succinate salt or a hydrochloride salt of the isocytosine derivative to be tested for its effect on contractions of uterine tissue was added to the bath. Figures 1-9 are kymographic records of contractions of the strip of uterine tissue before and after addition to the bath of the comtaining no isocytosine derivative. That portion 4 of Figures 1-9 after the letter I) represents contractions as they return t normal and after the uterine strip is no longer in contact with a-compound being tested for its effect on contractions of uterine tissue.

Figure 1 shows the addition of milligrams of the succinate salt of compound I to the bath produced an almost immediate effect on the contractions of th uterine tissue which amounted to a substantially complete cessation of contractions. Figure 2 shows the addition of 5 milligrams of the succinate salt of compound II caused a rapid diminishing of the contractions of the strip of uterine tissue followed by an almost complete cessation of contractions and an appreciable lowering of the tonus of the issue. Compound II formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid. Figure 3 shows that the addition to the bath of 5 milligrams of compound III in the form of its hydrochloride salt produced a gradual decreas in-amplitude of contractions of the uterine strip followed by a short period when the uterine tissue was not contracting. Figure 4 shows the addition to the bath of 5 milligrams of compound IV in the form of its hydrochloride salt produced a marked decrease in amplitude of contractions of the uterine tissue and a slight decreasein tonus, as well as a slight decrease in frequency. of contractions. Figure 5 shows the addition of 5 milligrams of the succinate salt of compound V produced an immediate cessation of contractions of the strip of uterine tissue and a slight lowering of tonus of the tissue. Figure 6 shows the addition of 5 milligrams of the succinate salt of compound VI produced a very rapid decline in amplitude of contractions and a substantiallowering of tonus of the strip of uterine tissue. Frequency of contractions of the tissue was increased. Compound VI formed a succinate salt in which four molecules of this compound were combined with five molecules of succinic acid. Figures '7, 8, and 9 show only slight effects on the uterine tissue result from the addition to the bath of the sesquisuccinate salts of compounds VII, VIII, and IX. Figure 7 shows the addition of milligrams of the sesquisuccinate salt of compound VII pro duced a slight decrease of amplitude of contractions and Figures 8 and 9 show the addition of 10 milligrams of the sesquisuccinate salts of compounds VIII and IX, respectively, to the bath produced a slight increase in amplitude of contractions and a slight increase in tonus of the uterine muscular tissue; however, compounds VII, and VIII and IX had .no appreciable. elfect on the frequency of contractions of the uterine muscular tissue.

Tonus is a natural property of muscle and'is a measure of degree of contraction independent of external influences. The degree of contraction produced by a stimulant depends upon the level of tonus, and, therefore, some investigators 4 have defined tonus as the resistance offered to extension.

Amplitude may be defined as the height of a contraction wave measured from the base level to the peak of the wave; base level being the average lower level of the contractions.

Frequency is the number of contraction waves in a unit time period.

Derivatives of isocytosine, such as 2-amino-4- dialkylaminoethoxypyrimidine and 2-amino-4- dialkylaminoethoxy-S-methylpyrimidine may be prepared by reacting 2-amino-4-chloropyrimidin or 2-amino-4-chloro-6-methylpyrimidine,

-respectively, with a sodium salt of a dialkylami- 'noethanol.

EXAMPLE I Preparation of 2 -amino-4-.diisobutylaminocaribou/pyrimidine Twenty-five parts of sodium metal were slowly added to 200 parts of diisobutylaminoethanol, dissolved in 500 parts of xylene. Twelve hundred parts of benzene were then added to the resulting sodium salt of diisobutylaminoethanol. One hundred twenty-nine parts of 2-amino-4-chloropyrimidine were added to the above solution-and during the addition the solution was cooled sufficiently to maintain the temperature at C. After the addition was complete, the reaction mixture was refluxed forone hour and cooled and then parts of water containing 10 parts of dissolved sodium hydroxide were added with stirring to the cooled reaction mixture. At this point two layers were formed and the organic layer was decanted. dried over anhydrous potassium carbonate, and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of 108l12 C. and a pressure of 0.001 mm. of mercury. One hundred seventy-two parts of 2- amino4-diisobutylaminoethoxypyrimidine were obtained.

A water-soluble succinate salt of the compound prepared above was made by dissolving 3.1 grams of free base and 1.4 grams of succinic acid in 12 cc. of boiling acetone. Upon cooling the acetone solution, a succinate salt of the pyrimidine base precipitated and was recrystallized from 10 cc. of hot acetone. 3.4 grams of the succinate salt of the pyrimidine base having a melting point of 98-99 C. were obtained and this crystalline salt had the following formula: V

(C14H26N4'O) (C4H604) EXAMPLE 11' Preparation of Z-amz'rio 4 diisobutylaminoethoxy-fi-methylpyrimidine Twenty-five parts of sodium metal were slowly added to 200 parts of diisobutylaminoethanol, dissolved in 500 parts'of xylene. Twelve hundred parts of benzene were then added to the resulting sodium salt of diisobutylaminoethanol. One hundred forty-three parts of 2-amino-4-chloro- 6-methylpyrimidine were added to the above solution and during the addition the solution was cooled suniciently to maintain the temperature at 80 C. After the addition was complete, the reaction mixture was refluxed for one hour and cooled and then 100 parts of water containing 10 parts of dissolvedsodium hydroxide were added with stirring to the cooled reaction mixture. After stirring had been stopped, two layers were formed and the organic layer was decanted, dried over anhydrous potassium carbonate and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of 100-110 C. and a pressure of 0.001 mm. of mercury. 160 parts of Z-amino 4 diisobutylaminoethoxy 6 methylpyrimidine were obtained.

A water-soluble succinate salt of the pyrimidine base was made by dissolving 4.1 grams of the pyrimidine base and 1.7 grams of succinic acid in 10 cc. of boiling acetone. Upon cooling the acetone solution, a white solid precipitated and it was removed and recrystallized from hot acetone. 3.5 grams of the recrystallized material were obtained and had a melting point of 99-100 C. The crystalline succinate salt of the pyrimidine base had the following formula:

(CH28N40) ((3411604) What is claimed is: l. A compound having the structural formula NH? O in which R. and R each is selected from the group 6 of alkyl radicals consisting of an isobutyl radical and alkyl radical having at least five and less than nine carbon atoms, and in which R" is selected from the group of radicals consisting of hydrogen and methyl.

2. A compound according to claim 1 in which R and R are each an isobutyl radical and R is hydrogen.

3. A compound according to claim 1 in which R and R are each a normal amyl radical and R" is hydrogen.

4. A compound according to claim 1 in which R. and R are each an isoamyl radical and R" is hydrogen.

5. A compound according to claim 1 in which R and R are each an isobutyl radical and R," is a methyl radical.

6. A compound according to claim 1 in which R and R. are each a normal amyl radical and R" is a methyl radical.

WILLIAM OROSHNIK.

REFERENCES CITED The following references are of record in the file of this patent:

Sutherland et al.: J. Org. Chem. 14, 235-238 (1949).

Braker et al.: J. Am. Chem. Soc. '69, 307243078 (1947). 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 